1. Field of the Invention
The present invention relates to water-soluble glycosides of vitamins A, E and K, and their use as pharmacological agents and nutritional additives.
2. Brief Description of the Prior Art
Deficiency or excessive intake of the fat-soluble vitamins A, E and K is usually accompanied by a number of severe and prolonged diseases. Thus, for example, deficiency of vitamin A causes hyperkeratosis, xerophthalmia, keratomalacia, and night blindness, whereas hypervitaminosis of vitamin A is characterized by irritability and anorexia, weight loss, itching, fatigue, and other adverse reactions. Deficiency of vitamin E produces kwashiorkor, macrocytic and hemolytic anemia, whereas hypervitaminosis thereof causes such symptoms as skeletal muscle weakness, gastrointestinal disorders and disturbances of reproductive functions. Vitamin K deficiency causes hypoprothrombinemia.
These vitamins are therefore needed by humans and must be supplied to the body by exogenous sources, mainly vegetables. Usually vitamins are supplied by a well-balanced diet, and healthy individuals have no need to ingest extra amounts of them as medicines. In certain conditions, however, extra amounts are needed in order to cure or prevent certain of the previously mentioned deficiency syndromes.
Vitamin deficiency may result from either primary deficiencies such as inadequate diets, traumatic stresses and the like, or secondary condition deficiencies such as malabsorption (intestinal abnormality or chronic diarrhea), increased demand (during periods of pregnancy, lactation, growth and certain diseases) or reduced storage facilities (protein binding and transfer to the site of action). (See generally Korolkovas and Burkhalter "Essentials of Medicinal Chemistry," John Wiley & Sons, New York (1976), pp. 577 ff).
It has long been desired to make the fat-soluble vitamins more water-soluble so that they would be more easily absorbed by the human body. When a vitamin is relatively insoluble in an aqueous environment or in the gastrointestinal lumen, post-administration dissolution may become the rate limiting step in drug absorption. On the other hand, with water-soluble vitamins, dissolution will occur rapidly and thus facilitate transfer through the blood and to the site of activity. It would therefore be desirable to provide forms of these vitamins which are hydrophilic and/or water-soluble, yet preserve the normal biological properties of the water-insoluble drugs.
Various methods of solubilizing complex molecules are known in the prior art, but for the most part these have been unsuitable since it has also been necessary that the materials, once they are made water-soluble would be nontoxic and the solubilizing groups would be acceptable to the human system. For example, Zeidler et al, U.S. Pat. No. 4,186,207, describe the formulation of stable aqueous or aqueous alcoholic solutions of fat-soluble drugs containing hydroxyalkylester--and/or N-(hydroxyalkyl)-amide-hydroxylates. Schmidt, U.S. Pat. No. 4,271,196, describes colloidal aqueous vehicles useful for the solubilization of insoluble or slightly soluble medicaments and suitable for parenteral or local administration, by mixing the medicaments with pharmaceutical adjuvants and micelle-forming agents comprising short-chain lecithin and non-hemolytic lipids. Hiroyuki Mima, Bitamin (Kyoro) 26(1), 1-12 (1962), (also cited at Chemical Abstracts 15938b (1964)), shows the solubilization of vitamins A and D by preparing sucrose esters or raffinose esters in lieu of polyoxyethylene derivatives.
A number of specific chemical conjugates between vitamins A and E and water-solubilizing conjugative groups has been reported. Thus, Pitha (Journal of the National Cancer Institute, Vol. 65, 1011, November 1980; see also, Pitha, U.S. patent application Ser. No. 17,570, filed July 21, 1980, published Mar. 27, 1981, available through NTIA's Order No. PAT-APP L1007570), discloses water-soluble dextran-linked retinal (retinal is the aldehyde derived from vitamin A). Retinal and high molecular weight polymeric dextran (average molecular weight 40,000) conjugates were prepared, and their water solubility, as well as the water solubility of the complexes thereof with cyclodextrin were studied. Humphlett et al, U.S. Pat. No. 2,875,195, prepared aminoacid conjugates of vitamins A, B.sub.2, D.sub.2 and E by reacting the water-insoluble vitamins with an isocyanato ester and then hydrolyzing with a suitable basic material. When taken internally, the normal hydrolytic cleavage of the solubilized vitamin results in aminoacids which are acceptable to the human system. Cawley et al, U.S. Pat. No. 2,680,749, describe water-soluble vitamin E-active polyethylene glycol esters of tocopheryl acid esters via esterification of tocopheryl acid esters with polyethylene glycol. Spanel, U.S. Pat. No. 3,151,127, describes vitamin E conjugates with ascorbate, which are water-soluble and suitable for oral administration and parenteral injections.
A number of water-soluble principles having vitamin D activity have been extracted from various plants such as Solanum malacoxylon and Cestrum diurnum (see for example Haussler, M. R. et al, Life Sciences, Vol. 18, 1049-1056 (1956), Napoli, J. L. et al, The Journal of Biological Chemistry, 252:2580-2583 (1977), Hughes, N. R. et al, Nature, 268:347-349 (1977), or Matsumoto, Hasimo, JC-MSU 5:4 (1977)). These principles release active (water-insoluble) 1 .alpha.,25-dihydroxy vitamin D.sub.3 upon treatment with a mixture of enzymes which generally includes glycosidases. The results are consistent with the belief that they may be vitamin D glycosides. The evidence also shows that the molecular weights of the principles are considerably greater than 1,000 (Humphreys, D. J., Nature New Biology, 246:155 (1973)), implying that the principle would in that case contain more than 3 glycosidic units. In any event, no analogous natural water-soluble principles for vitamins A, E or K have been described in the literature.
A series of well-defined synthetic lower molecular weight vitamin D glycosides are described in co-pending U.S. patent application Ser. No. 249,922, filed on Apr. 1, 1981, by the present co-inventors at the U.S. Patent and Trademark Office, now U.S. Pat. No. 4,410,515, and which is in its entirety, herein incorporated by reference.
A need continues to exist for biologically active, well-defined nontoxic water-soluble preparations of vitamins A, E and K.